Can anti-viral agents show us the viral cause


Sedaghat N, Etemadifar M. Revisiting the antiviral theory to explain interferon-beta’s effectiveness for relapsing multiple sclerosis. Mult Scler Relat Disord. 2022;67:104155. doi: 10.1016/j.msard.2022.104155

Treatments with interferon-beta (IFNβ) – a cytokine with established antiviral effects – were initially considered for multiple sclerosis (MS), as epidemiological data pointed towards a viral aetiological agent for it. Later, when no specific agent was found for MS, theories explaining IFNβ’s mechanism of action (MOA) relied on anti-inflammatory mechanisms, which did not explain its ineffectiveness for disease progression independent of relapse activity (PIRA) in progressive forms of MS. Now, with new evidence backing the Epstein-Barr virus (EBV) as a conditional agent in MS aetiopathogenesis as well as linking the reactivation of a wide range of other Herpesviridae with MS onset/relapse, it may be time to revisit the antiviral theory to explain IFNβ’s MOA, look at the evidence from the past two decades from that perspective, and address the paucity of knowledge with new direct studies and discussions.

My take on this is somewhat different and rather than using the anti-viral activity of say beta interferons and teriflunomide to suggest that EBV is a central viral origin of MS, I would argue the data says that if they are such good anti-virals then it says MS is not viral mediated. I realise that the ProfGs have been spinning this alternative story, I think it needs clarification.

(1) The history of it that I remember was that when there was a new agent available, it was tried in MS as there was nothing available.

Most failed before beta interferon came along. I bet many of these failures resulted from them being tested in secondary progressive MS, which does not respond well. However many of these studies were probably shots in the dark as the trials were not optimised for success, and I suspect that if we know then what we know now many studies could have been positive.

Now the idea that MS has a viral aetiology is not new and we know that interferons are anti-viral and therefore you can create the logic that anti-viral agents should inhibit MS.

(2) However, remember there are three main types of interferon. Interferon beta into the spine was positive, later it was shown to be active systmemically , but interferon alpha didn’t work and gamma interferon appeared to make MS worse. So what does this say about the viral origin?. If they are are all anti-viral then they should be equally effective or they should have differential activity on the causative virus.

(3) Next up the beta interferon should be a poor anti-viral. Why because if it were a potent anti-viral and the virus was the causative problem, then beta interferon should be much better than it is. Sure it may work very well in some individuals, but for many indviduals it is not that good.

(4) The same argument can be leveled at other MS drugs….ProfG used to be suggest that teriflunomide was a good anti-viral that could target EBV. However if that is true why is it not the best treatment since sliced-bread. Likewise we have anti-viral T cells transplant therapy, which many of you are pinning hopes on. However, either the trials designs are not great or their efficacy as anti-virals are not that great because agian the clinical effectsare not that miraculous. We know that teriflunomide is worse at controlling MS than other MS disease modifying treatments because head to heads have been done in trials.

(5) We have had many mechanisms ascribed to glatiramer acetate and these have changed during the years as new mechanisms have been identified. I have no issues with this is what every mechanism you are looking at it has to be modulated weakly inmost individuals, because this would then reflect the clinical activity. If it were fantastic at inhibiting a mechaninism then surely you would exclude it as being of central importance because otherwise the efficacy would be great in every body.

(6) Given the variability in agents they should differentially target the virus of interest what is it. However good are they at inhibiting EBV?

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  • There have been some interesting case studies of HIV+ MS patients who contracted HIV after developing MS.
    It appears that the anti-retroviral agents seem to do a number on EBV as well.
    Nobody knows if it’s the depletion followed by reconstitution once the anti-retrovirals are doing their thing.
    Or if the anti-retroviral is also able to target a process that EBV needs to flare up – so it can’t flare up.

    The faulty anti-EBV antibodies that don’t quite fit EBV, also fit myelin and then instigate an additional anti-EBV T-cell response on top (not the case for correct anti-EBV antibodies) seem to then sort themselves out.

    Mechanism? No idea, I am just hypothesising. But it seems to me that we already have a few antiviral and antiretroviral agents that could be good candidates for add-on treatment trials.

    • yes it was done… mentioned we have been here before, same virus different targets found and the big question is why dont you get liver failure as the glialcam is expressed in the liver as its realname is Hepacam? maybe it was explained in the video but I havent watched it yet

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